Targeting Alzheimer's Disease: Evaluating the Efficacy of C-1 Functionalized N-Aryl-Tetrahydroisoquinolines as Cholinergic Enzyme Inhibitors and Promising Therapeutic Candidates.

We have synthesized 22 C-1 functionalized-N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives showing biological activities towards cholinergic enzymes. Synthesis was performed using visible-light-promoted photo-redox chemistry, starting from a common intermediate, and the application of this synthetic methodology drastically simplified synthetic routes and purification of desired compounds. All synthesized derivates were divided into four groups based on the substituents in the C-1 position, and their inhibition potencies towards two cholinergic enzymes, acetyl- and butyrylcholinesterase were evaluated. Most potent derivatives were selected, and kinetic analysis was further carried out to obtain insights into the mechanisms of inhibition of these two enzymes. Further validation of the mode of inhibition of cholinergic enzymes by the two most potent THIQ compounds, 3c and 3i, was performed using fluorescence-quenching titration studies. Molecular docking studies further confirmed the proposed mechanism of enzymes' inhibition. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the selected most potent derivatives were performed using Swiss ADME tool. This was followed by UPLC-assisted log P determination and in vitro BBB permeability studies performed in order to assess the potential of the synthesized compounds to pass the BBB.

Visible-light promoted photoredox catalysis in flow: addition of biologically important α­amino radicals to michael acceptors.

Visible light promoted photoredox catalyzed formation of α-amino radicals from cyclic tertiary amine compounds and their subsequent addition to Michael acceptors performed in flow conditions allowed access to a wide range of functionalized N-aryl-substituted tetrahydroisoquinolines (THIQs) and N-aryl-substituted tetrahydro-ß-carbolines (THBCs). Visible light in conjunction with Ru(bpy)3Cl2 photocatalyst allowed the formation and high reactivities of α-amino radicals in flow conditions at room temperature. These reactions gave valuable products with high efficiencies; some previously unavailable reaction pathways photo or thermal reaction conditions; i.e. direct synthesis of 1-substituted (THBCs) via α-amino radical path were successfully realized in flow. The use of custom-made FEP tube microreactor proved to be the key to succesfull α-amino-radical formation and overall reaction performance in flow. Three types of light transparent custom-made microfluidic devices were tested, among them glass/silicon and FEP type reactor showed very good results in the conversion of tested compounds. Plausible reaction mechanism is proposed in accordance with known principles of photo activation of tertiary amines. Visible light promoted C(sp3)-H functionalization of N-aryl-protected tetrahydroisoquinolines and N-aryl-protected tetrahydro-ß-carbolines in microflow conditions via a-amino radical pathway with various coupling partners in excellent yields and efficiencies.

Stereoselective Construction of Fluorinated Quaternary Stereogenic Centers via an Organocatalytic Asymmetric exo-Selective Diels-Alder Reaction in the Presence of Water.

A catalytic, asymmetric Diels-Alder reaction of α-fluoro α,ß-unsaturated aldehydes and cyclopentadiene was developed using diarylprolinol silyl ether as an organocatalyst. The reaction proceeds in toluene with trifluoroacetic acid as an additive (condition A). Perchloric acid salt of diarylprolinol silyl ether also promotes the reaction using water as a reaction medium (condition B). In both cases, excellent exo-selectivity and enantioselectivity were obtained with generation of a fluorinated quaternary chiral center.

"Soft Protein Corona" as the Stabilizer of the Methionine-Coated Silver Nanoparticles in the Physiological Environment: Insights into the Mechanism of the Interaction.

The study of the interactions between nanoparticles (NPs) and proteins has had a pivotal role in facilitating the understanding of biological effects and safe application of NPs after exposure to the physiological environment. Herein, for the first time, the interaction between L-methionine capped silver nanoparticles (AgMet), and bovine serum albumin (BSA) is investigated in order to predict the fate of AgMet after its contact with the most abundant blood transport protein. The detailed insights into the mechanism of interaction were achieved using different physicochemical techniques. The UV/Vis, TEM, and DLS were used for the characterization of the newly formed "entity", while the kinetic and thermodynamic parameters were utilized to describe the adsorption process. Additionally, the fluorescence quenching and synchronous fluorescence studies enabled the prediction of the binding affinity and gave us insight into the influence of the adsorption on the conformation state of the BSA. According to the best of our knowledge, for the first time, we show that BSA can be used as an external stabilizer agent which is able to induce the peptization of previously agglomerated AgMet. We believe that the obtained results could contribute to further improvement of AgNPs' performances as well as to the understanding of their in vivo behavior, which could contribute to their potential use in preclinical research studies.

1,2,3,4-Tetrahydroisoquinoline Derivatives as a Novel Deoxyribonuclease I Inhibitors.

Herein we report an assessment of 24 1,2,3,4-tetrahydroisoquinoline derivatives for potential DNase I (deoxyribonuclease I) inhibitory properties in vitro. Four of them inhibited DNase I with IC50 values below 200 µM. The most potent was 1-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)propan-2-one (2) (IC50 =134.35±11.38 µM) exhibiting slightly better IC50 value compared to three other active compounds, 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]-1-phenylethan-1-one (15) (IC50 =147.51±14.87 µM), 2-[2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one (18) (IC50 =149.07±2.98 µM) and 2-[6,7-dimethoxy-2-(p-tolyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]cyclohexan-1-one (22) (IC50 =148.31±2.96 µM). Cytotoxicity assessment of the active DNase I inhibitors revealed a lack of toxic effects on the healthy cell lines MRC-5. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, His 134, Asn 170, Tyr 211, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Observed interactions would be beneficial for the discovery of new active 1,2,3,4-tetrahydroisoquinoline-based inhibitors of DNase I, but might also encourage researchers to further explore and utilize potential therapeutic application of DNase I inhibitors, based on a versatile role of DNase I during apoptotic cell death.

Synthesis and analysis of 4-oxothiazolidines as potential dual inhibitors of deoxyribonuclease I and xanthine oxidase.

In this study, seven new 4-oxothiazolidine derivatives were synthesized and assayed, along 7 known derivatives, for inhibitory properties against deoxyribonuclease I (DNase I) and xanthine oxidase (XO) in vitro. Among tested compounds, (5Z)-Ethyl-2-(2-(cyanomethylene)-4-oxothiazolidin-5-yliden)acetate (6) exhibited inhibitory activity against both enzymes (DNase I IC50 = 67.94 ± 5.99 µM; XO IC50 = 98.98 ± 13.47 µM), therefore being the first reported dual inhibitor of DNase I and XO. Observed DNase I inhibition qualifies compound 6 as the most potent small organic DNase I inhibitor reported so far. Derivatives of 2-alkyliden-4-oxothiazolidinone (1) inhibited DNase I below 200 µM, while the other tested 4-oxothiazolidine derivatives remained inactive against both enzymes. The molecular docking and molecular dynamics simulations into the binding sites of DNase I and XO enzyme allowed us to clarify the binding modes of this 4-oxothiazolidine derivative, which might aid future development of dual DNase I and XO.

Visible light promoted photoredox C(sp3)-H bond functionalization of tetrahydroisoquinolines in flow.

A merger of organocatalysis and visible light photoredox catalysis performed in flow allowed access to a wide range of functionalized N-aryl-substituted tetrahydroisoquinolines (THIQs) in a formal C-H oxidation/Mannich reaction. Strecker type functionalization and copper-catalyzed alkynylation of several N-aryl-substituted THIQs were also successfully performed in flow, giving valuable products with high efficiencies. The use of custom-made porous polymeric type microreactors proved to be crucial regarding the C-H oxidation step and overall reaction performance.

Deoxyribonuclease I Inhibitory Properties, Molecular Docking and Molecular Dynamics Simulations of 1-(Pyrrolidin-2-yl)propan-2-one Derivatives.

Deoxyribonuclease I (DNase I) inhibitory properties of two 1-(pyrrolidin-2-yl)propan-2-one derivatives were examined in vitro. Determined IC50 values of 1-[1-(4-methoxyphenyl)pyrrolidin-2-yl]propan-2-one (1) (192.13±16.95 µM) and 1-[1-(3,4,5-trimethoxyphenyl)pyrrolidin-2-yl]propan-2-one (2) (132.62±9.92 µM) exceed IC50 value of crystal violet, used as a positive control, 1.89- and 2.73-times, respectively. Compounds are predicted to be nontoxic and to have favorable pharmacokinetic profiles, with high gastrointestinal absorption and blood-brain barrier permeability. Molecular docking and molecular dynamics simulations suggest that interactions with Glu 39, Glu 78, Arg 111, Pro 137, Asp 251 and His 252 are an important factor for inhibitors affinity toward the DNase I. Determined inhibitory properties along with predicted ADMET profiles and observed interactions would be beneficial for the discovery of new active 1-(pyrrolidin-2-yl)propan-2-one-based inhibitors of DNase I.

Aminoalcoholate-driven tetracopper(II) cores as dual acetyl and butyrylcholinesterase inhibitors: Experimental and theoretical elucidation of mechanism of action.

Three coordination compounds featuring different types of tetracopper(II) cores, namely [O ⊂ Cu4{N(CH2CH2O)3}4(BOH)4][BF4]2 (1), [Cu4(µ4-H2edte)(µ5-H2edte)(sal)2]n·7nH2O, (H4edte = N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine, H2sal = salicylic acid) (2), and [{Cu4(µ3-Hbes)4(µ-hba)}K(H2O)3]n, H3bes = N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (3), were assayed for their potency to inhibit the acetyl (AChE) and butyrylcholinesterase (BuChE) enzymes aiming to test these compounds as potential dual inhibitors in the treatment of Alzheimer's disease. All the investigated compounds showed a strong inhibitory potency toward both enzymes with IC50 values in micromolar range of concentration; compound 1 displayed the most potent inhibitory behaviour toward both enzymes. The mechanism of the AChE and BuChE inhibition was examined by enzyme kinetic measurements. The obtained kinetic parameters, Vmax and Km indicated an uncompetitive type of inhibition of both enzymes by compound 1. For the other two compounds a non-competitive inhibition mode was observed. To get further insight into the mechanism of action and to elucidate binding modes in details we examined the interactions of 1-3 with acetylcholinesterase, using molecular docking approach. Grid based docking studies indicated that these compounds can bind to peripheral anionic site (PAS) of the AChE with Ki values in micromolar range. Moreover, blind docking revealed the capability of investigated compounds to bind to new allosteric site (i.e. binding site II) distinct from PAS. Showing that these Cu-based compounds can act as new allosteric inhibitors of AChE and identifying novel allosteric binding site on AChE represents a significant contribution toward the design of novel and more effective inhibitors of AChE.

Synthesis and DNase I inhibitory properties of new benzocyclobutane-2,5-diones.

Aim: Eight new benzocyclobutane-2,5-diones (1a-1h) were synthesized, and their inhibitory properties against bovine pancreatic DNase I were examined in vitro. Methods & results: Compounds 1a-1h were synthesized using photocycloaddition of duroquinone with various phenyl-substituted ethylenes in the presence of 18W compact fluorescent lamp (visible light). Two compounds, 1,3,4,6-tetramethyl-7-phenylbicyclo[4.2.0]oct-3-ene-2,5-dione (1a) and 1,3,4,6-tetramethyl-7-p-tolylbicyclo[4.2.0]oct-3-ene-2,5-dione (1b) inhibited DNase I in a noncompetitive manner with IC50 values below 150 µM and showed to be more potent DNase I inhibitors than crystal violet, used as a positive control. In order to analyze potential binding sites for the studied compounds with DNase I, molecular docking study was performed. Conclusion: The studied benzocyclobutane-2,5-diones offer a good starting point for a design of new DNase I inhibitors.

Dehydrogenative C(sp3)-H bond functionalization of tetrahydroisoquinolines mediated by organic oxidants under mild conditions.

The organocatalyzed Mannich reaction of unsubstituted and N-aryl-substituted tetrahydroisoquinolines (THIQs) and the Strecker reaction of several N-aryl-substituted THIQs through dehydrogenative C(sp3)-H bond functionalization (cross-dehydrogenative coupling) promoted by organic single electron oxidants DDQ and IBX are presented. The C-H oxidation/Mannich reaction of less reactive N-aryl substituted pyrrolidines is achieved via metal catalyzed photoredox catalysis. Operationally simple procedures provide desired products in an effective and time preserving manner.

Synthesis and DNase I inhibitory properties of some 4-thiazolidinone derivatives.

Twelve new thiazolidinones were synthesized and, together with 41 previously synthesized thiazolidinones, evaluated for inhibitory activity against deoxyribonuclease I (DNase I) in vitro. Ten compounds inhibited commercial bovine pancreatic DNase I with an IC50 below 200 µM and showed to be more potent DNase I inhibitors than crystal violet (IC50 = 365.90 ± 47.33 µM), used as a positive control. Moreover, three compounds were active against DNase I in rat liver homogenate, having an IC50 below 200 µM. (3-Methyl-1,4-dioxothiazolidin-2-ylidene)-N-(2-phenylethyl)ethanamide (41) exhibited the most potent DNase I inhibition against both commercial and rat liver DNase I with IC50 values of 115.96 ± 11.70 and 151.36 ± 15.85 µM, respectively. Site Finder and molecular docking defined the thiazolidinones interactions with the most important catalytic residues of DNase I, including the H-acceptor interaction with residues His 134 and His 252 and/or H-donor interaction with residues Glu 39 and Asp 168. The three most active compounds against both commercial and rat liver DNase I (31, 38, and 41) exhibited favorable physico-chemical, pharmacokinetic, and toxicological properties. These observations could be utilized to guide the rational design and optimization of novel thiazolidinone inhibitors. Thiazolidinones as novel DNase I inhibitors could have potential therapeutic applications due to the significant involvement of DNase I in the pathophysiology of many disease conditions.

Asymmetric Diels-Alder Reaction of α-Substituted and ß,ß-Disubstituted α,ß-Enals via Diarylprolinol Silyl Ether for the Construction of All-Carbon Quaternary Stereocenters.

The asymmetric Diels-Alder reaction of α-substituted acrolein proceeds in the presence of the trifluoroacetic acid salt of trifluoromethyl-substituted diarylprolinol silyl ether to afford the exo-isomer with both excellent diastereoselectivity and high enantioselectivity. In the Diels-Alder reaction of a ß,ß-disubstituted α,ß-unsaturated aldehyde, good exo-selectivity and excellent enantioselectivity was obtained when the perchloric acid salt of the bulky triisopropyl silyl ether of trifluoromethyl substituted diarylprolinol was employed as an organocatalyst in the presence of water. In both cases, all-carbon quaternary stereocenters are constructed enantioselectively.

Asymmetric epoxidation of α-substituted acroleins catalyzed by diphenylprolinol silyl ether.

Asymmetric epoxidation of α-substituted acroleins with hydrogen peroxide has been catalyzed by diphenylprolinol diphenylmethylsilyl ether to afford α-substituted-ß,ß-unsubstituted-α,ß-epoxy aldehyde with excellent enantioselectivity and the generation of a chiral quaternary carbon center. The method was applied to a short synthesis of (R)-methyl palmoxirate.

Application of iridium catalyzed allylic substitution reactions in the synthesis of branched tryptamines and homologues via tandem hydroformylation-Fischer indole synthesis.

Combination of enantioselective allylation reactions with a tandem hydroformylation-Fischer indole synthesis sequence as a highly diversity-oriented strategy for the synthesis of tryptamines and homologues was explored. This modular approach allows the substituents at C3 of the indole core, the type of the amine moiety, and the distance of the amine moiety to the indole core in the final synthetic step to be defined. The starting materials required for the hydroformylation step were synthesized via iridium catalyzed enantioselective allylic substitution reactions in high yields and excellent enantioselectivities. The Rh catalyzed hydroformylation step in the presence of phenyl hydrazine, allows the in situ formed aldehyde to be trapped as the hydrazone. Subsequent acid catalyzed indolization furnishes the desired indole structures in moderate to good yields.

Syntheses of tetrahydro-beta-carbolines via a tandem hydroformylation-Pictet-Spengler reaction. Scope and limitations.

A novel one-pot synthesis of tetrahydro-beta-carboline systems via tandem hydroformylation-Pictet-Spengler reaction starting from olefins and aryl ethylamines is described. This tandem procedure allows fast and convenient synthesis of various substituted tetrahydro-beta-carbolines.

A novel access to tetrahydro-beta-carbolines via one-pot hydroformylation/fischer indole synthesis: rearrangement of 3,3-spiroindoleninium cations.

The two component one-pot hydroformylation/Fischer indole synthesis sequence of 2,5 dihydropyrroles and phenyl hydrazines allows a facile and convenient access to tetrahydro-beta-carbolines in moderate to good yields.